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Rapid and accurate remethylation of DNA in Dnmt3a-deficient hematopoietic cells with restoration of DNMT3A activity.
- Source :
-
Science Advances . 2/2/2024, Vol. 10 Issue 5, p1-18. 18p. - Publication Year :
- 2024
-
Abstract
- Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of Dnmt3a or Dnmt3b (or both enzymes) or expressing the dominant-negative Dnmt3aR878H mutation [R882H in humans; the most common DNMT3A mutation found in acute myeloid leukemia (AML)]. Using these cells as substrates, we defined DNA remethylation after overexpressing wild-type (WT) DNMT3A1, DNMT3B1, DNMT3B3 (an inactive splice isoform of DNMT3B), or DNMT3L (a catalytically inactive "chaperone" for DNMT3A and DNMT3B in early embryogenesis). Overexpression of DNMT3A for 2 weeks reverses the hypomethylation phenotype of Dnmt3a-deficient cells or cells expressing the R878H mutation. Overexpression of DNMT3L (which is minimally expressed in AML cells) also corrects the hypomethylation phenotype of Dnmt3aR878H/+ marrow, probably by augmenting the activity of WT DNMT3A encoded by the residual WT allele. DNMT3L reactivation may represent a previously unidentified approach for restoring DNMT3A activity in hematopoietic cells with reduced DNMT3A function. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 23752548
- Volume :
- 10
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Science Advances
- Publication Type :
- Academic Journal
- Accession number :
- 175184263
- Full Text :
- https://doi.org/10.1126/sciadv.adk8598